The purpose of the Neurogenetics Branch is to investigate the causes of hereditary neurological diseases, with the goal of developing effective treatments for these disorders. Particular areas of research interest include the polyglutamine expansion diseases (Huntington's disease, Kennedy's disease, and spinocerebellar ataxia), spinal muscular atrophy, Charcot-Marie-Tooth disease, muscular dystrophy, hereditary motor neuron disease, and Friedreich's ataxia. The disease mechanisms are studied in cell culture and other model systems. A genetic outreach program allows the identification and characterization of patients and families with hereditary neurological diseases. A trial of idebenone treatment in Friedreich's ataxia was recently completed, and a trial of dutasteride treatment for Kennedy's disease is in progress. Further therapeutic trials are anticipated. Specific research accomplishments in the past year include the following: (1) We further characterized the mechanism of neuronal death in cell culture and Drosophila models of polyglutamine disease, investigating the role of profilin and the beneficial effects of IGF-1. (2) We further characterized the biochemical effects and clinical and pathological manifestations of a mutation in the transport protein dynactin in an autosomal dominant form of motor neuron disease. (3) We further characterized the manifestations of motor neuronopathy due to mutations in glycyl-tRNA synthetase. (4) We reported further studies of X-linked Charcot-Marie-Tooth disease in transgenic mice. (5) We further characterized the effects of histone acetylation and histone deacetylase inhibitors on the expression of SMN, the gene that is mutated in spinal muscular atrophy, and we demonstrated a therapeutic response in a mouse model of the disease. (6) We completed a phase 2 study of idebenone treatment in Friedreich's ataxia comparing high dose, low dose, and placebo treatment. (7) We started a placebo-controled phase 2 study of dutasteride treatment in Kennedy's disease.